A substantial number of the more than 45 million postmenopausal US women will develop dementia or cognitive impairment. Our Perimenopause in Brain Aging and Alzheimer's Disease Program Project seeks to discover the biological transformations occurring in the brain during the perimenopausal transition which can result in phenotypes predictive of risk for development of Alzheimer's disease (AD) pathology and to identify the mechanisms by which these changes occur, and translate these discoveries to determine the optimal timing and strategies for preventing conversion to the perimenopausal at-risk phenotype. Project 4 will characterize biological profiles from the perimenopausal and postmenopausal periods, and evaluate the association of these profiles with cognition in women who are in eariy vs. late menopause. Project 4 will (1) determine whether biomarkers hypothesized to be important in the perimenopausal period and in AD characterize the postmenopausal human female in eariy vs. later menopause; (2) determine whether and to what extent these biomarkers are associated with cognition; and (3) evaluate whether administration of menopausal hormone therapy will modify these markers. Project 4 will use data and stored tissue samples from the NIA-funded Eariy versus Late Intervention Trial with Estrogen (ELITE) (R01AG-024154) trial to test four hypotheses: (1) The perimenopause transition results in the bioenergetic and inflammatory phenotype consistent with biomarkers of Alzheimer's disease risk; (2) the perimenopause transition will result in multiple phenotypes, subgroups of which will predict risk of developing biomarkers of Alzheimer's disease; (3) the perimenopause transition is a critical window that determines ovarian hormone response and their role in prevention vs. increased risk of developing eariy biomarkers of AD; and (4) ovarian hormone and bioenergetic interventions can modify development of biomarkers of Alzheimer's disease in the perimenopausal at-risk phenotype. This Project will work closely with Analytic Core and Administrative Core on processing samples and data, and with Projects 1-3 on bioenergetic, inflammatory, and dietary analyses. RELEVANCE (See instructions): More than 60% of Alzheimer's disease (AD) patients are women. This phase of our Perimenopause Program Project seeks to evaluate, identify and prevent perimenopause-related brain changes predictive of increased AD risk. Project 4 will determine whether flushing and the timing and duration of perimenopause are associated with increased risk of cognitive decline. Project 4 will evaluate the impact of hormonal and dietary interventions on cognitive function, and identify a treatment window to reduce risk of cognitive decline.